1. Field of the Invention
The present invention concerns inhibition of the production of proinflammatory cytokine interleukin-17 (IL-17) by T cells, using an antagonist of interleukin-23 (IL-23). The invention further concerns the use of IL-23 antagonists in the treatment of inflammatory diseases characterized by the presence of elevated levels of IL-17.
2. Description of the Related Art
IL-17 is a T cell derived pro-inflammatory molecule that stimulates epithelial, endothelial and fibroblastic cells to produce other inflammatory cytokines and chemokines including IL-6, IL-8, G-CSF, and MCP-1 (S. Aggarwal, A. L. Gurney, J Leukoc Biol 71, 1 (2002); Z. Yao et al., Immunity 3, 811 (1995); J. Kennedy et al., J Interferon Cytokine Res 16, 611 (1996); F. Fossiez et al., J Exp Med 183, 2593 (1996); A. Linden, H. Hoshino, M. Laan, Eur Respir J 15, 973 (2000); X. Y. Cai, C. P. Gommoll, Jr., L. Justice, S. K. Narula, J. S. Fine, Immunol Lett 62, 51 (1998); D. V. Jovanovic et al., J Immunol 160, 3513 (1998); and M. Laan et al., J Immunol 162, 2347 (1999)).
IL-17 also synergizes with other cytokines including TNF-α and IL-1β to further induce chemokine expression (Jovanovic et al., supra, and M. Chabaud, F. Fossiez, J. L. Taupin, P. Miossec, J Immunol 161, 409 (1998)). Levels of IL-17 are found to be significantly increased in rheumatoid arthritis (RA) synovium (S. Kotake et al., J Clin Invest 103, 1345 (1999); and M. Chabaud et al., Arthritis Rheum 42, 963 (1999)), during allograft rejection (M. A. Antonysamy et al., Transplant Proc 31 (1999); M. A. Antonysamy et al., J Immunol 162, 577 (1999); C. C. Loong, C. Y. Lin, W. Y. Lui, Transplant Proc 32 (2000); and H. G. Hsieh, C. C. Loong, W. Y. Lui, A. Chen, C. Y. Lin, Transpl Int 14, 287 (2001)), and in other chronic inflammatory diseases including multiple sclerosis (K. Kurasawa et al., Arthritis Rheum 43, 2455 (2000)) and psoriasis (C. Albanesi et al., J Invest Dermatol 115, 81 (2000), and B. Homey et al., J Immunol 164, 6621 (2000)). Although clearly produced by activated T cells, previous reports have not provided clear classification of IL-17 within the paradigm of Th1 and Th2 polarized cytokine profiles.
IL-23 is a heterodimeric cytokine, sharing a subunit, termed p40, with interleukin-12 (IL-12), that combines with a unique subunit, p19 (B. Oppmann et al., Immunity 13, 715 (2000)). IL-23 has been reported to promote the proliferation of T cells, in particular memory T cells (D. M. Frucht, Sci STKE 2002 Jan. 8; 2002(114):PE1). Transgenic p19 mice have been recently described to display profound systemic inflammation and neutrophilia (M. T. Wiekowski et al., J Immunol 166, 7563 (2001)).
No correlation has so far been established between the expression and biological roles of the IL-17 and IL-23 cytokines.